Difluoromethylornithine inhibits urogastrone stimulation of neomucosal growth

Abstract

Urogastrone (UG) stimulates the growth of intestinal neomucosa on patched intestinal defects. This effect may be dependent on increased polyamine biosynthesis. The aim of this study was to determine if difluoromethylornithine (DFMO), a specific inhibitor of polyamine synthesis, would inhibit urogastrone stimulation of neomucosal growth. Twenty-four New Zealand white rabbits (2.1–2.9 kg) had 2 × 5-cm ileal defects patched with adjacent cecal serosal surface. Group I ( n = 6) served as controls. Group II ( n = 6) received UG 1.5 μg/kg/hr subcutaneously. Group III ( n = 6) took 2% DFMO orally. Group IV ( n = 6) received the same doses of UG and DFMO simultaneously. Animals were sacrificed 7 days after patching to assess neomucosal growth. Urogastrone infusion resulted in significantly greater neomucosal coverage (54 ± 4%) and neomucosal surface area (236 ± 18 mm 2) in the Group II animals. Neomucosal coverage and contraction of the intestinal defects and neomucosal surface area were similar in the other three groups. Crypt cell production rate (15.5 ± 2.0 cells/hr) and disaccharidase activity were also significantly greater in Group II than in the other groups. DFMO alone (Group III) resulted in a significantly lower ornithine decarboxylase (ODC) activity, polyamine content, and crypt cell production rate. Group IV animals had lower ODC activity but not lower polyamine content or crypt cell production rate. UG resulted in a significant increase in neomucosal growth. DFMO prevented this stimulatory effect and inhibited ornithine decarboxylase activity. The stimulation of neomucosal growth by UG is dependent, at least in part, on increased polyamine biosynthesis.